Single Administration of Xoma 358, an Insulin Receptor Attenuator, Improves Post-Meal and Nighttime Hypoglycemia Profiles in Post Gastric Bypass Hypoglycemia (PGBH) Patients
Presentation Number: OR14-6
Date of Presentation: April 3rd, 2017
Kirk W. Johnson*1, Allan Gordon1, Ann C. Neale1, Adrian Vella2, Clare Jung Eun Lee3, Allison B. Goldfine4, Helen M. Lawler5, Richard Millstein6, Stella Costante-Hamm1, Padma Bezwada1 and Paul D. Rubin1
1XOMA (US) LLC, Berkeley, CA, 2Mayo Clinic, Rochester, MN, 3Johns Hopkins University, Baltimore, MD, 4Research Division, Joslin Diabetes Center, Boston, MA, 5Univ. Colorado School of Medicine, Denver, CO, 6Univ. of Colorado School of Medicine, Denver, CO
Severe postprandial hypoglycemia with hyperinsulinemia has emerged as an increasingly worrisome complication of bariatric surgery (CJ Lee et al., Obesity 24:1342, 2016). We have described the discovery and initial healthy volunteer clinical trial of a novel pharmacotherapy, XOMA 358, which is a human monoclonal antibody that binds allosterically to the insulin receptor and attenuates its activation by insulin (ENDO 2015, abstract #3060; mAbs 6:262, 2014). We now report data from post-gastric bypass patients with established postprandial hypoglycemia treated with single intravenous (IV) infusions of XOMA 358 at 3, 6, or 9 mg/kg with 3-5 subjects in each dose cohort (total N=12).
Participants were enrolled and admitted to a clinical research unit for a baseline period of 4-5 days followed by XOMA 358 infusion administered over 30 min, with safety, tolerability, serum drug pharmacokinetic, and pharmacodynamics evaluations over the next 11 days as well as follow-up safety visits extending 43 days post-dose. Pharmacological activity was assessed by monitoring glycemic status and serum biomarkers (e.g. insulin, C-peptide, ketones) at fasting and postprandial intervals throughout the study period as well as during nighttime fasting periods. Furthermore, mixed meal tolerance tests (MMTT) with oral BOOSTRintake and blood and serum biomarker analyses lasting 4 hrs thereafter were performed at defined baseline and post-dose study days. Glucose levels were additionally monitored by 24 hr continuous glucose monitoring (CGM).
XOMA 358 infusions were generally well-tolerated without any drug-related SAEs. Across all three dose levels, peak post-meal test glucose levels were higher following XOMA 358 compared to baseline. The duration of bedside glucose levels remaining >60 mg/dL following meals was prolonged over the 3-5 days post-treatment in all dose cohorts, and extended to Day 11 in the 9 mg/kg cohort. Moreover, the 9 mg/kg cohort tended to show both longer time until glucose nadir (nearly twice that of baseline) and higher glucose nadirs compared to the lower dose cohorts. Interestingly, CGM analyses at baseline revealed that at least half of the patients also exhibited mean glucose levels between midnight and 8am below normal averages (≥90 mg/dL). In these patients, XOMA 358 increased mean overnight glucose levels by ~20% (p<0.05). In the week following dosing, fasting beta-hydroxybutyrate levels were two- to three-fold higher than baseline at all three dose levels, thus representing an additional biomarker supporting attenuated insulin action by XOMA 358 in these PGBH patients. Together, these findings support continued development of XOMA 358 as a first-in-class pharmacotherapy for PGBH.
Disclosure: KWJ: Vice President, XOMA Corp. AG: Clinician, XOMA Corp. ACN: Clinical Researcher, XOMA Corp. SC: Clinical Researcher, XOMA Corp. PB: Clinical Researcher, XOMA Corp. PDR: Management Position, XOMA Corp. Nothing to Disclose: AV, CJEL, ABG, HML, RM